The use of acupuncture has been developing an increasing acceptance as a form of medical therapy to treat pain and other disease processes, supported by a growing number of clinical trials. Recent experimental studies in both animal and humans have begun to demonstrate some measurable physiologic effects that are associated with acupuncture, suggesting the possibility of a neurophysiologic explanation. In addition, brain research continues to uncover a complex set of endogenous neurologic control systems, such that it has become clear that the brain plays a major role in the modulation of pain perception and control. If acupuncture can be demonstrated to have a consistent effect on specific areas of the brain, it will become possible to explore the potential efficacy of acupuncture based on measurable neurophysiologic responses. The development of functional brain imaging has provided several methods of studying the activity of the human brain under controlled conditions. Functional imaging techniques that measure changes in cerebral blood flow (CBF) are thought to reflect focal increased activity in brain function. Single photon emission computed tomography (SPECT), and several methods of functional magnetic resonance imaging (f-MRI) begun to define the brain regions where changes in the CBF are associated with the experience of pain, with preliminary data on acupuncture as well. But consistent pathways and structures with pain and acupuncture have not been defined. In order to carefully explore the significance of changes that occur in CBF with acupuncture therapy, the brain scans should be correlated with clinical response in a clinical trial setting of a common, well defined, and easily diagnosed painful condition which has been shown to respond to acupuncture. A recently published controlled but unblinded clinical trial of osteoarthritis (OA) of the knee has shown some efficacy vs stand care, and is likely to be a good model. However, basic information is required about the specific model before trying to design a study larger definitive trial. The information required include: 1) If there are any consistent areas of the brain that show CBF changes when acupuncture is used in knee OA compared to identical acupuncture in normal subjects (without pain); 2) If there are consistent changes in the acupuncture treated knee OA group compared to a blinded control group treated with placebo acupuncture; and 3) since SPECT and f-MRI have substantially different risks and benefits for such a study, do both SPECT and f-MRI provide similar information. Defining the areas of interest and the techniques to use, will allow a comprehensive study of the effect on CBF of acupuncture therapy.